Neuroscience
-
Hippocampal neurogenesis and associated cognitive behaviors are regulated by a number of factors including stress, inflammation, and exercise. However, the interplay between these factors remains relatively unexplored, especially across the lifespan. In the current study, the effect of social isolation stress during the adolescent period on neurogenesis and hippocampal-dependent cognitive behaviors was examined. ⋯ The results from the current study demonstrate that social isolation stress during adolescence followed by intra-hippocampal exposure to the pro-inflammatory cytokine IL-1β in early adulthood produces deficits in both spontaneous alternations and novel object recognition. Exercise attenuated deficits in neurogenesis and novel object recognition in mice that had been exposed to the 'dual-hit' of stress and neuroinflammation. These findings indicate that adolescence represents a key period of the lifespan during which external factors such as stress and exercise can impact on hippocampal development, and may alter the response to challenges such as neuroinflammation in later life.
-
Excessive Glutamate (Glu) release may trigger excitotoxic cellular death by the activation of intracellular signaling pathways that transduce extracellular signals to the cell nucleus, which determines the onset of a death program. One such signaling pathway is the mitogen-activated protein kinases (MAPK), which is involved in both survival and cell death. Experimental evidences from the use of specific inhibitors supports the participation of some MAPK pathway components in the excitotoxicity mechanism, but the complete process of this activation, which terminates in cell damage and death, is not clearly understood. ⋯ Transcriptional changes were also investigated in 98 components of the MAPK pathway that are associated with cell damage. These results are an evidence of that repetitive use of MSG, in neonatal rats, induces cell damage-associated transcriptional changes of MAPK components, that might reflect a differential stage of both biochemical and molecular brain maturation. This work also suggests that some of the proteins evaluated such as phosphorylated retinoblastoma (pRb) protein, which was up-regulated, could regulate the response to excitotoxic through modulation of the process of re-entry into the cell cycle in the hippocampus of rats treated with MSG.
-
Children and adolescents have the highest rates of traumatic brain injury (TBI), with mild TBI (mTBI) accounting for most of these injuries. Adolescents are particularly vulnerable and often suffer from post-injury symptomologies that may persist for months. We hypothesized that the combination of resveratrol (RES), prebiotic fiber (PBF), and omega-3 fatty acids (docosahexaenoic acid (DHA)) would be an effective therapeutic supplement for the mitigation of mTBI outcomes in the developing brain. ⋯ A behavioral test battery designed to examine symptomologies commonly associated with mTBI was administered. Following the test battery, tissue was collected from the prefrontal cortex (PFC) and primary auditory cortex for Golgi-Cox analysis of spine density, and for changes in expression of 6 genes (Aqp4, Gfap, Igf1, Nfl, Sirt1, and Tau). 3S treatment altered the behavioral performance of sham animals indicating that dietary manipulations modify premorbid characteristics. 3S treatment prevented injury-related deficits in the longer-term behavior measures, medial prefrontal cortex (mPFC) spine density, and levels of Aqp4, Gfap, Igf1, Nfl, and Sirt1 expression in the PFC. Although not fully protective, treatment with the supplement significantly improved post-mTBI function and warrants further investigation.
-
Mutant SOD1 causes amyotrophic lateral sclerosis (ALS) by a dominant gain of toxicity. Previous studies have demonstrated therapeutic potential of mutant SOD1-RNAi delivered by intrathecal (IT) injection of recombinant adeno-associated virus (rAAV). However, optimization of delivery is needed to overcome the high degree of variation in the transduction efficiency and therapeutic efficacy. ⋯ To test how these effects influence the outcome of RNAi therapy, we used slow and fast IT injection to deliver rAAVrh10-GFP-amiR-SOD1, a rAAV vector that expresses GFP and an artificial miRNA targeting SOD1, in SOD1-G93A mice. Both slow and fast IT injection produced therapeutic efficacy but the slow injection trended slightly toward a better outcome than the fast injection. These results demonstrate that IT injection speed influences the predominance of gene delivery at different CNS sites and should be taken into consideration in future therapeutic trials involving IT injection.